Esophageal cancer is the sixth leading cause of cancer death worldwide and in American men. Adenocarcinoma, the prevalent type in the US, arises from Barrett's esophagus, a metaplastic change in the distal esophagus. Unfortunately, an understanding of signaling pathways that link the initiation of metaplasia to development of adenocarcinoma is lacking. Based on preliminary data, we hypothesize that aberrant Hedgehog pathway activation, necessary for normal foregut development, is a critical early event in the development of Barrett's metaplasia and continues in the progression to adenocarcinoma. With this proposal, we hope to determine if (1) Hedgehog pathway activation is a cause of Barrett's metaplasia, (2) acid and bile reflux can activate the Hedgehog pathway, (3) p63 is a downstream target of Hedgehog signaling which mediates epithelial transdifferentiation and (4) Hedgehog pathway specific inhibitors can prevent and/or treat esophageal adenocarcinoma in preclinical models. The long-term clinical objective of these studies is translating Hedgehog pathway inhibitors into a chemopreventive therapy for Barrett's esophagus and a targeted therapy for invasive adenocarcinoma. [unreadable] [unreadable] [unreadable] [unreadable]